101.Roupret, M., et al. A comparison of the performance of
microsatellite and methylation urine analysis for predicting the recurrence of urothelial cell carcinoma,
and definition of a set of markers by Bayesian network analysis. BJU Int, 2008. 101: 1448.

186.Oosterlinck, W., et al. A prospective European
Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing
transurethral resection followed by a single intravesical instillation of epirubicin or water in single
stage Ta, T1 papillary carcinoma of the bladder. J Urol, 1993. 149: 749.

231.Brausi, M., et al. Side effects of Bacillus
Calmette-Guerin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the
bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose
with full dose and 1 year with 3 years of maintenance BCG. Eur Urol, 2014. 65: 69.

232.Oddens, J.R., et al. Increasing age is not associated
with toxicity leading to discontinuation of treatment in patients with urothelial non-muscle-invasive
bladder cancer randomised to receive 3 years of maintenance bacille Calmette-Guerin: results from European
Organisation for Research and Treatment of Cancer Genito-Urinary Group study 30911. BJU Int, 2016. 118: 423.

250.Martinez-Pineiro, J.A., et al. Has a 3-fold decreased
dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis
bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol, 2005. 174: 1242.

257.Sylvester, R.J., et al. Bacillus calmette-guerin
versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a
meta-analysis of the published results of randomized clinical trials. J Urol, 2005. 174: 86.

264.BCG-Unresponsive Nonmuscle Invasive Bladder Cancer:
Developing Drugs and Biologics for Treatment Guidance for Industry. 2018, U.S. Department of Health and
Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER).

1.INTRODUCTION

1.1.Aim and scope

This overview represents the updated European Association of Urology (EAU)
Guidelines for Non-muscle-invasive Bladder Cancer (NMIBC), TaT1 and carcinoma in situ (CIS). The information presented is limited to
urothelial carcinoma, unless specified otherwise. The aim is to provide practical recommendations on
the clinical management of NMIBC with a focus on clinical presentation and recommendations.

Separate EAU Guidelines documents are available addressing upper
tract urothelial carcinoma (UTUC) [1],
muscle-invasive and metastatic bladder cancer (MIBC) [2],
and primary urethral carcinoma [3].
It must be emphasised that clinical guidelines present the best evidence available to the experts,
but following guideline recommendations will not necessarily result in the best outcome. Guidelines
can never replace clinical expertise when making treatment decisions for individual patients, but
rather help to focus decisions - also taking personal values and preferences/individual
circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal
standard of care.

1.2.Panel composition

The EAU Guidelines Panel on NMIBC consists of an international multidisciplinary
group of clinicians, including urologists, uro-oncologists, a pathologist and a statistician.
Members of this Panel have been selected based on their expertise and to represent the professionals
treating patients suspected of suffering from bladder cancer. All experts involved in the production
of this document have submitted potential conflict of interest statements which can be viewed on the
EAU website Uroweb: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.

1.3.Available publications

A quick reference document (Pocket guidelines) is available, both in print and as
an app for iOS and Android devices. These are abridged versions which may require consultation
together with the full text version. Several scientific publications are available, the latest
publication dating to 2016 [4],
as are a number of translations of all versions of the EAU NMIBC Guidelines. All documents are
accessible through the EAU website Uroweb: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.

1.4.Publication history and summary of changes

1.4.1.Publication history

The EAU Guidelines on Bladder Cancer were first published in 2000. This 2019 NMIBC
Guidelines document presents a limited update of the 2018 publication.

1.4.2.Summary of changes

Additional data has been included throughout this document text. In particular in
sections:

5.4.3 - Multiparametric magnetic resonance imaging (mpMRI);

5.10.2 - Surgical and technical aspects of tumour resection: a new paragraph on TUR best
practice has been included;

A new recommendation has been added to:

Section 5.14 - Summary of evidence and guidelines for transurethral resection of the bladder,
biopsies and pathology report

Recommendation

Strength
rating

Outpatient
fulguration or laser vaporisation of small papillary recurrences can be used in patients
with a history of TaG1/LG tumours.

Weak

7.3.2 - Recurrence and failure after intravesical bacillus Calmette-Guérin (BCG) immunotherapy:
this section, including Table 7.2 (Categories of unsuccessful treatment with intravesical BCG)
has been expanded.

2.METHODS

2.1.Data Identification

For the 2019 NMIBC Guidelines, new and relevant evidence has been identified,
collated and appraised through a structured assessment of the literature.

A broad and comprehensive scoping exercise covering all areas of
the NMIBC Guidelines was performed. Excluded from the search were basic research studies, case
series, reports and editorial comments. Only articles published in the English language, addressing
adults, were included. The search was restricted to articles published between May 24th 2017 and June 8th 2018.
Databases covered by the search included Pubmed, Ovid, EMBASE and the Cochrane Central Register of
Controlled Trials and the Cochrane Database of Systematic Reviews. After deduplication, a total of
456 unique records were identified, retrieved and screened for relevance.

For Chapters 3-6 (Epidemiology, Aetiology and Pathology, Staging and Classification
systems, Diagnosis, Predicting disease recurrence and progression) references used in this text are
assessed according to their level of evidence (LE) based on the 2009 Oxford Centre for
Evidence-Based Medicine (OCEBM) Levels of Evidence [5].
For the Disease Management and Follow-up chapters (Chapters 7 and 8) a system modified from the 2009
CEBM levels of evidence is being used [5].

For each recommendation within the guidelines there is an accompanying online
strength rating form the bases of which is a modified GRADE methodology [6,7].
Each strength rating form addresses a number of key elements namely:

the overall quality of the evidence which exists for the recommendation [5];

the magnitude of the effect (individual or combined effects);

the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);

the balance between desirable and undesirable outcomes;

the impact of patient values and preferences on the intervention;

the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of
each recommendation. The strength of each recommendation is represented by the words ‘strong’ or
‘weak’ [7].
The strength of each recommendation is determined by the balance between desirable and undesirable
consequences of alternative management strategies, the quality of the evidence (including certainty
of estimates), and nature and variability of patient values and preferences. The strength rating
forms will be available online.

3.EPIDEMIOLOGY, AETIOLOGY AND

PATHOLOGY

3.1.Epidemiology

Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male
population worldwide, while it drops to eleventh when both genders are considered [8].
The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.0 for men and 2.2 for
women [8].
In the European Union the age-standardised incidence rate is 19.1 for men and 4.0 for women [8].
In Europe, the highest age-standardised incidence rate has been reported in Belgium (31 in men and
6.2 in women) and the lowest in Finland (18.1 in men and 4.3 in women) [8].

Worldwide, the BC age-standardised mortality rate (per 100,000
person/years) was 3.2 for men vs. 0.9 for women in 2012 [8].
Bladder cancer incidence and mortality rates vary across countries due to differences in risk
factors, detection and diagnostic practices, and availability of treatments. The variations are,
however, partly caused by the different methodologies used and the quality of data collection [9].
The incidence and mortality of BC has decreased in some registries, possibly reflecting the
decreased impact of causative agents [10].

Approximately 75% of patients with BC present with a disease
confined to the mucosa (stage Ta, CIS) or submucosa (stage T1); in younger patients (< 40) this
percentage is even higher [11].
Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and lower
risk of cancer-specific mortality compared to T2-4 tumours [8,9].

3.2.Aetiology

Tobacco smoking is the most important risk factor for BC, accounting for
approximately 50% of cases [9,10,12,13]
(LE: 3). Environmental exposure to tobacco smoke is also associated with an increased risk for BC
[9].
Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are renally
excreted.

Occupational exposure to aromatic amines, polycyclic aromatic
hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for BC,
accounting for about 10% of all cases. This type of occupational exposure occurs mainly in
industrial plants, which process paint, dye, metal and petroleum products [9,10,14,15].
In developed industrial settings, these risks have been reduced by work-safety guidelines,
therefore, chemical workers no longer have a higher incidence of BC compared to the general
population [9,14,15].

While family history seems to have little impact [16]
and, to date, no overt significance of any genetic variation for BC has been shown; genetic
predisposition has an influence on the incidence of BC via its impact on susceptibility to other
risk factors [9,17-21].
This has been suggested to lead to familial clustering of BC with an increased risk for first- and
second-degree relatives (hazard ratio: 1⁄4 1.69, 95% confidence interval [CI]: 1⁄4, 1.47 to 1.95, p
< .001) [22].

Although the impact of drinking habits is uncertain, the
chlorination of drinking water and subsequent levels of trihalomethanes are potentially
carcinogenic, also exposure to arsenic in drinking water increases risk [9,23]
(LE: 3). The association between personal hair dye use and risk remains uncertain; an increased risk
has been suggested in users of permanent hair dyes with a slow NAT2 acetylation phenotype [9].
Dietary habits seem to have little impact [24-27].

Exposure to ionizing radiation is connected with increased risk; weak association was also suggested for cyclophosphamide and pioglitazone [9,23,28] (LE: 3). The impact of metabolic factors (body mass index, blood pressure, plasma glucose, cholesterol and triglycerides) is uncertain [29]. Schistosomiasis, a chronic endemic cystitis based on recurrent infection with a parasitic trematode, is also a cause of BC [9] (LE: 3).

3.3.Pathology

The information presented in this text is limited to urothelial carcinoma, unless
otherwise specified.

3.4.Summary of evidence for epidemiology, aetiology and
pathology

Several risk factors connected
with the risk of BC diagnosis have been identified.

3

4.STAGING AND CLASSIFICATION SYSTEMS

4.1.Definition of non-muscle-invasive bladder cancer

Papillary tumours confined to the mucosa and invading the lamina propria are
classified as stage Ta and T1, respectively, according to the Tumour, Node, Metastasis (TNM)
classification system [30].
Flat, high-grade tumours that are confined to the mucosa are classified as CIS (Tis). These tumours
can be treated by transurethral resection of the bladder (TURB), eventually in combination with
intravesical instillations and are therefore grouped under the heading of NMIBC for therapeutic
purposes. The term “Non-muscle-invasive BC” presents an overall group definition and all tumours
must be defined according to their T-stage and histological grade (see below). The term ‘superficial
BC’ should no longer be used as it is incorrect.

4.2.Tumour, Node, Metastasis Classification (TNM)

The 2009 TNM classification approved by the Union International Contre le Cancer
(UICC) was updated in 2017 (8th Edn.), but with no changes in
relation to bladder tumours (Table 4.1) [30].

4.3.T1 subclassification

The depth and extent of invasion into the lamina propria (T1 substaging) has been
demonstrated to be of prognostic value in retrospective cohort studies [31,32]
(LE: 3). Its use is recommended by the most recent 2016 World Health Organization (WHO)
classification [33].
The optimal system to substage T1 remains to be defined [33,34].

In 2004, the WHO and the International Society of Urological Pathology published a
new histological classification of urothelial carcinomas which provides a different patient
stratification between individual categories compared to the older 1973 WHO classification [35,36]
(Tables 4.2 and 4.3, Figure 4.1). Recently an update of the 2004 WHO grading classification was
published [33],
but the following guidelines are still based on the 1973 and 2004 WHO classifications since most
published data rely on these two classifications [35-37].

A recent systematic review and meta-analysis did not show that the 2004/2016
classification outperforms the 1973 classification in prediction of recurrence and progression [37]
(LE: 2a).

There is a significant shift of patients between the prognostic categories of both
systems, for example an increase in the number of HG patients (WHO 2004/2016) due to inclusion of
some G2 patients with their better prognosis compared to the G3 category (WHO 1973) [37].
As the 2004 WHO system has not been fully incorporated into prognostic models yet, long term
individual patient data in both classification systems are needed.

Figure 4.1: Stratification of tumours according to grade in the WHO 1973 and
2004 classifications [38]*

Histologic Spectrum of urothelial carcinoma [UC]

*1973 WHO Grade 1 carcinomas have been reassigned to papillary
urothelial neoplasm of low malignant potential (PUNLMP) and low-grade (LG) carcinomas in
the 2004 WHO classification, and Grade 2 carcinomas to LG and high-grade (HG)
carcinomas. All 1973 WHO Grade 3 carcinomas have been reassigned to HG carcinomas
(Reproduced with permission from Elsevier).

4.5.Carcinoma in situ and its classification

Carcinoma in situ is a flat, high-grade, non-invasive urothelial carcinoma. It can be missed or misinterpreted as an inflammatory lesion during cystoscopy if not biopsied. Carcinoma in situ is often multifocal and can occur in the bladder, but also in the upper urinary tract (UUT), prostatic ducts, and prostatic urethra [39].

4.6.Inter- and intra-observer variability in staging and
grading

There is significant variability among pathologists for the diagnosis of CIS, for
which agreement is achieved in only 70-78% of cases [41]
(LE: 2a). There is also inter-observer variability in the classification of stage T1 vs. Ta tumours
and tumour grading in both the 1973 and 2004 classifications. The general conformity in staging and
grading is between 50% and 60% [42-45]
(LE: 2a). The published comparisons have not clearly confirmed that the WHO 2004 classification
provides better reproducibility than the 1973 classification [37,42,45-47].

4.7.Further pathology parameters

The presence of lymphovascular invasion (LVI) in TURB specimens is associated with
an increased risk of pathological upstaging and worse prognosis [48-52]
(LE: 3).

Molecular markers and their prognostic role have been
investigated [61-65].
These methods, in particular complex approaches such as the stratification of patients based on
molecular classification are promising, but are not yet suitable for routine application [66,67].

4.8.Summary of evidence and guidelines for bladder
cancer classification

Summary of evidence

LE

The depth of invasion
(staging) is classified according to the TNM classification.

2a

Papillary tumours confined to
the mucosa and invading the lamina propria are classified as stage Ta and T1, respectively.
Flat, high-grade tumours that are confined to the mucosa are classified as CIS (Tis).

2a

For histological
classification of NMIBC, both the WHO 1973 and 2004 grading systems are used.

2a

Recommendations

Strength
rating

Use the 2017 TNM
system for classification of the depth of tumour invasion (staging).

Strong

Use both the 1973 and
2004/2016 WHO grading systems for histological classification.

Strong

Do not use the term
‘superficial bladder cancer’.

Strong

Mention the tumour
stage and grade whenever the terminology NMIBC is used in individual cases.

Strong

5.DIAGNOSIS

5.1.Patient history

A comprehensive patient history is mandatory.

5.2.Signs and symptoms

Haematuria is the most common finding in NMIBC. Visible haematuria was found to be
associated with higher stage disease compared to nonvisible haematuria at first presentation [68].
Carcinoma in situ might be suspected in patients with lower
urinary tract symptoms, especially irritative voiding.

5.3.Physical examination

A focused urological examination is mandatory although it does not reveal
NMIBC.

5.4.Imaging

5.4.1.Computed tomography urography and intravenous urography

Intravenous urography (IVU) is an alternative if CT is not
available [70]
(LE: 2b), but particularly in muscle-invasive tumours of the bladder and in UTUCs, CT urography
gives more information than IVU (including status of lymph nodes and neighbouring organs).

The necessity to perform a baseline CT urography or IVU once a
bladder tumour has been detected is questionable due to the low incidence of significant findings
obtained [71-73]
(LE: 2b). The incidence of UTUCs is low (1.8%), but increases to 7.5% in tumours located in the
trigone [72]
(LE: 2b). The risk of UTUC during follow up increases in patients with multiple- and high-risk
tumours [74]
(LE: 2b).

5.4.2.Ultrasound

Ultrasound (US) may be performed as an adjunct to physical examination as it has
moderate sensitivity to a wide range of abnormalities in the upper and lower urinary tract. It
permits characterisation of renal masses, detection of hydronephrosis, and visualisation of
intraluminal masses in the bladder, but cannot rule out all potential causes of haematuria [75,76]
(LE: 3). It cannot reliably exclude the presence of UTUC and cannot replace CT urography.

5.4.3.Multiparametric magnetic resonance imaging

The role of multiparametric magnetic resonance imaging (mpMRI) has not yet been
established in BC diagnosis and staging. A standardised methodology of MRI reporting in patients
with BC was recently published but requires validation [77].

A diagnosis of CIS cannot be made with imaging methods alone (CT
urography, IVU, US or MRI) (LE: 4).

5.5.Urinary cytology

The examination of voided urine or bladder-washing specimens for exfoliated cancer
cells has high sensitivity in G3 and high-grade tumours (84%), but low sensitivity in G1/LG tumours
(16%) [78].
The sensitivity in CIS detection is 28-100% [79]
(LE: 1b). Cytology is useful, particularly as an adjunct to cystoscopy, in patients with HG/G3
tumours. Positive voided urinary cytology can indicate an urothelial tumour anywhere in the urinary
tract; negative cytology, however, does not exclude the presence of a tumour.

A standardised reporting system redefining urinary cytology diagnostic categories
was published in 2016 by the Paris Working Group [82]:

adequacy of urine specimens (Adequacy);

negative for high-grade urothelial carcinoma (Negative);

atypical urothelial cells (AUC);

suspicious for high-grade urothelial carcinoma (Suspicious);

high-grade urothelial carcinoma (HGUC);

low-grade urothelial neoplasia (LGUN).

The Paris system for reporting urinary cytology has been validated in several
retrospective studies [83,84].

Urine collection should respect the recommendation provided in Section 5.9. One cytospin slide from the sample is usually sufficient [85]. In patients with suspicious cytology repeat investigation is advised [86] (LE: 2b).

5.6.Urinary molecular marker tests

Driven by the low sensitivity and low negative predictive value of urine cytology,
numerous urinary tests have been developed [87].
None of these markers have been accepted for diagnosis or follow-up in routine practice or clinical
guidelines.

The following conclusions can be drawn regarding the existing tests:

Sensitivity is usually higher at the cost of lower specificity, compared to urine cytology [88-93]
(LE: 3).

More complex biomarkers are emerging which reflect different molecular pathways [87].

5.7.Potential application of urinary cytology and
markers

The following objectives of urinary cytology or molecular tests must be
considered.

5.7.1.Screening of the population at risk of bladder cancer

The application of haematuria dipstick, FGFR3, NMP22 or UroVysion in BC screening
in high-risk populations has been reported [105,106].
The low incidence of BC in the general population and the short lead-time impair feasibility and
cost-effectiveness [103,106].
Routine screening for BC is not recommended [103,105,106].

5.7.2.Exploration of patients after haematuria or other symptoms suggestive of bladder cancer (primary detection)

It is generally accepted that none of the currently available tests can replace
cystoscopy. However, urinary cytology or biomarkers can be used as an adjunct to cystoscopy to
detect missed tumours, particularly CIS. In this setting, sensitivity for high-grade tumours and
specificity are particularly important.

5.7.3.Surveillance of non-muscle-invasive bladder cancer

Research has been carried out into the usefulness of urinary cytology vs. markers
in the follow up of NMIBC [94,95,107].

5.7.3.1.Follow-up of high-risk
non-muscle-invasive bladder cancer

High-risk tumours should be detected early in follow up and the percentage of
tumours missed should be as low as possible. Therefore, the best surveillance strategy for these
patients will continue to include frequent cystoscopy and cytology.

To reduce the number of cystoscopy procedures, urinary markers should be able to
detect recurrence before the tumours are large and numerous. The limitation of urinary cytology and
current urinary markers is their low sensitivity for low-grade recurrences [89,95]
(LE: 1b).

According to current knowledge, no urinary marker can replace cystoscopy during follow up or lower cystoscopy frequency in a routine fashion. One prospective randomised study found that knowledge of positive test results (microsatellite analysis) can improve the quality of follow-up cystoscopy [108] (LE: 1b),
supporting the adjunctive role of a non-invasive urine test performed prior to follow-up cystoscopy
[108] (see Section 8.1).

5.8.Cystoscopy

The diagnosis of papillary BC ultimately depends on cystoscopic examination of the
bladder and histological evaluation of sampled tissue by either cold-cup biopsy or resection.
Carcinoma in situ is diagnosed by a combination of cystoscopy,
urine cytology, and histological evaluation of multiple bladder biopsies [109].

Cystoscopy is initially performed as an outpatient procedure. A
flexible instrument with topical intraurethral anaesthetic lubricant instillation results in better
compliance compared to a rigid instrument, especially in men [110,111]
(LE: 1b).

Figure 5.1: Bladder diagram

1 = Trigone

6 = Anterior wall

2 = Right ureteral orifice

7 = Posterior wall

3 = Left ureteral orifice

8 = Dome

4 = Right wall

9 = Neck

5 = Left wall

10 = Posterior urethra

5.9.Summary of evidence and guidelines for the primary
assessment of non-muscle-invasive bladder cancer

Summary of evidence

LE

The diagnosis of bladder
cancer depends on cystoscopy examination.

1

Urinary cytology has high
sensitivity in high-grade tumours including carcinoma in situ.

2b

Recommendations

Strength
rating

Take a patient
history, focusing on urinary tract symptoms and haematuria.

Strong

Use renal and bladder
ultrasound and/or computed tomography-intravenous urography (CT-IVU) during the initial
work-up in patients with haematuria.

Strong

Once a bladder tumour
has been detected, perform a CT urography in selected cases (e.g., tumours located in
the trigone, multiple- or high-risk tumours).

Strong

Perform cystoscopy in
patients with symptoms suggestive of bladder cancer or during surveillance. It cannot be
replaced by cytology or by any other non-invasive test.

Strong

In men, use a
flexible cystoscope, if available.

Strong

Describe all
macroscopic features of the tumour (site, size, number and appearance) and mucosal
abnormalities during cystoscopy. Use a bladder diagram (Figure 5.1).

Strong

Use voided urine
cytology as an adjunct to cystoscopy to detect high-grade tumour.

Strong

Perform cytology on
at least 25 mL fresh urine or urine with adequate fixation. Morning urine is not suitable
because of the frequent presence of cytolysis.

Strong

Use the Paris system
for cytology reporting.

Strong

5.10.Transurethral resection of TaT1 bladder tumours

5.10.1.Strategy of the procedure

The goal of TURB in TaT1 BC is to make the correct diagnosis and completely remove
all visible lesions. It is a crucial procedure in the diagnosis and treatment of BC. TURB should be
performed systematically in individual steps [112]
(see Section 5.14).

The operative steps necessary to achieve a successful TURB include identifying the
factors necessary to assign disease risk (number of tumours, size, multifocality, characteristics,
concern for the presence of CIS, recurrent vs. primary tumour), clinical stage (bimanual examination
under anaesthesia, assignment of clinical tumour stage), adequacy of the resection (visually
complete resection, visualisation of muscle at the resection base), and presence of complications
(assessment for perforation) [113].
To measure the size of the largest tumour, one can use the end of cutting loop, which is
approximately 1 cm wide as a reference. The characteristics of the tumour are described as sessile,
nodular, papillary or flat.

5.10.2.Surgical and technical aspects of tumour resection

A complete resection is essential to achieve a good prognosis [114].
A complete resection can be achieved by either fractioned or en-bloc resection [112].

Piecemeal resection in fractions (separate resection of the exophytic part of the tumour, the
underlying bladder wall and the edges of the resection area) provides good information about the
vertical and horizontal extent of the tumour [115]
(LE: 2b).

En-bloc resection using monopolar or bipolar current,
Thulium-YAG or Holmium-YAG laser is feasible in selected exophytic tumours. It provides high
quality resected specimens with the presence of detrusor muscle in 96-100% of cases [112,116-119]
(LE: 1b).

The technique selected is dependent on the size and location of the tumour and
experience of the surgeon.

5.10.2.2.Evaluation
of resection quality

It has been confirmed that the absence of detrusor muscle in the specimen is
associated with a significantly higher risk of residual disease, early recurrence and tumour
understaging [120]
(LE: 1b). The presence of detrusor muscle in the specimen is considered as the surrogate criterion
of the resection quality and is required (except in TaG1/LG tumours).

It has been shown that surgical experience can improve TURB
results, which supports the role of teaching programmes [121].
Virtual training on simulators is an emerging approach [122].
Its role in the teaching process still needs to be established.

5.10.2.3.Monopolar and bipolar resection

Compared to monopolar resection, bipolar resection has been introduced to reduce
the risk of complications (e.g., bladder perforation due to obturator nerve stimulation) and to
produce better specimens for the pathologist. Currently, the results remain controversial [123-126].

5.10.2.4.Office-based fulguration and laser
vaporisation

In patients with a history of small, TaLG/G1 tumours, fulguration or laser
vaporisation of small papillary recurrences on an outpatient basis can reduce the therapeutic burden
[127,128]
(LE: 3). There are no prospective comparative studies assessing the oncological outcomes.

5.10.2.5.Resection of small papillary bladder tumours
at the time of transurethral resection of the prostate

Only limited, retrospective, data exist on the outcome of incidentally detected
papillary bladder tumour during cystoscopy as the initial step of transurethral resection of the
prostate. Provided these tumours are papillary by aspect, rather small and not extensively
multifocal, it seems feasible to resect these tumours and continue with the resection of the
prostate. However, no exact risk-assessment can be provided [129,130].

5.10.3.Bladder biopsies

Carcinoma in situ can present as a
velvet-like, reddish area, indistinguishable from inflammation, or it may not be visible at all. For
this reason biopsies from abnormal urothelium should be taken. However, in patients with positive
urine cytology, or with a history of HG/G3 NMIBC and in tumours with non-papillary appearance,
mapping biopsies from normal-looking mucosa is recommended.

To obtain representative mapping of the bladder mucosa, biopsies
should be taken from the trigone, bladder dome, right, left, anterior and posterior bladder wall [131,132].
If equipment is available, photodynamic diagnosis (PDD) is a useful tool to target the biopsy.

5.10.4.Prostatic urethral biopsies

Involvement of the prostatic urethra and ducts in men with NMIBC has been reported.
Palou et al. [133]
showed that in 128 men with T1G3 BC, the incidence of CIS in the prostatic urethra was 11.7% [133]
(LE: 2b). The risk of prostatic urethra or duct involvement is higher if the tumour is located at
the trigone or bladder neck, in the presence of bladder CIS and multiple tumours [134]
(LE: 3b). Based on this observation, a biopsy from the prostatic urethra is necessary in some cases
(see recommendation in Section 5.14) [133,135].

5.11.New methods of tumour visualisation

As a standard procedure, cystoscopy and TURB are performed using white light.
However, the use of white light can lead to missing lesions that are present but not visible, which
is why new technologies are being developed.

5.11.1.Photodynamic diagnosis (fluorescence cystoscopy)

Photodynamic diagnosis is performed using violet light after intravesical
instillation of 5-aminolaevulinic acid (ALA) or hexaminolaevulinic acid (HAL). It has been confirmed
that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for
the detection of malignant tumours, particularly for CIS [136,137]
(LE: 1a). In a systematic review and meta-analysis, PDD had higher sensitivity than white light
endoscopy in the pooled estimates for analyses at both the patient-level (92% vs.71%) and
biopsy-level (93% vs. 65%) [137].
A prospective randomised trial did not confirm a higher detection rate in patients with known
positive cytology before TURB [138].

Photodynamic diagnosis had lower specificity than white-light
endoscopy (63% vs. 81%) [137].
False-positivity can be induced by inflammation or recent TURB and during the first three months
after BCG instillation [139,140]
(LE: 1a).

The beneficial effect of ALA or HAL fluorescence cystoscopy on
recurrence rate in patients with TURB was evaluated by prospective randomised trials. A systematic
review and analysis of 14 RCTs including 2,906 patients, six using 5-ALA and nine HAL, demonstrated
a decreased risk of BC recurrence in the short and long term. There were, however, no differences in
progression and mortality rates. The analysis demonstrated inconsistency between trials and
potential susceptibility to performance and publication bias [141]
(LE: 1a).

One RCT has shown a reduction in recurrence and progression with
fluorescence guided TURB as compared to white light TURB [142].
These results need to be validated by further studies.

5.11.2.Narrow-band imaging

In narrow-band imaging (NBI), the contrast between normal urothelium and
hyper-vascular cancer tissue is enhanced. Cohort studies as well as one small single-institution
prospective randomised trial have demonstrated improved cancer detection by NBI flexible cystoscopy
and NBI-guided biopsies and resection [143-146]
(LE: 3b). An RCT assessed the reduction of recurrence rates if NBI is used during TURB. Although
overall results of the study were negative, a benefit after three and twelve months was observed for
low-risk tumours (pTa/LG, < 30 mm, no CIS) [147]
(LE: 1b).

5.12.Second resection

5.12.1.Detection of residual disease and tumour upstaging

The significant risk of residual tumour after initial TURB of TaT1 lesions has been
demonstrated [114]
(LE: 1b).

A recently published SR analysing data of 8,409 patients with
Ta/HG and T1 BC demonstrated a 51% risk of disease persistence and an 8% risk of understaging in T1
tumours. The analysis also showed a high risk of residual disease in Ta tumours, but this analysis
was based on a limited number of cases only. Most of the residual lesions were detected at the
original tumour location [148]
(LE: 1a).

Another meta-analysis of 3,556 patients with T1 tumours showed
that the prevalence rate for residual tumours and upstaging to invasive disease after TURB remained
high in a subgroup with detrusor muscle in the resection specimen. In the subgroup of 1,565 T1
tumours with detrusor muscle present, persistent tumour was found in 58% and understaging occurred
in 11% of cases [149].

In a retrospective evaluation of a large multi-institutional
cohort of 2,451 patients with BCG-treated T1G3/HG tumours (a second resection was performed in 935
patients), the second resection improved RFS, progression-free survival (PFS) and overall survival
(OS) only in patients without detrusor muscle in the specimen from the initial resection [157]
(LE: 3).

5.12.3.Timing of second resection

Retrospective evaluation showed that a second resection performed 14-42 days after
initial resection provides longer RFS and PFS compared to second resection performed after 43-90
days [158]
(LE: 3). Based on these arguments, a second TURB is recommended in selected cases two-six weeks
after initial resection (for recommendations on patient selection, see Section 5.14).

5.12.4.Recording of results

The results of the second resection (residual tumours and understaging) reflect the
quality of the initial TURB. As the goal is to improve the quality of the initial TURB, the results
of the second resection should be recorded.

5.13.Pathology report

Pathological investigation of the specimen(s) obtained by TURB and biopsies is an
essential step in the diagnosis and treatment decision-making process for BC [159].
Close co-operation between urologists and pathologists is required. A high quality of resected and
submitted tissue and clinical information is essential for correct pathological assessment. The
presence of sufficient muscle is necessary for the correct assignment of the T category. To obtain
all relevant information, the specimen collection, handling and evaluation, should respect the
recommendations provided below (see Section 5.14) [160].
In difficult cases, an additional review by an experienced genitourinary pathologist should be
considered.

5.14.Summary of evidence and guidelines for
transurethral resection of the bladder, biopsies and pathology report

Summary of evidence

LE

Transurethral resection of the
bladder (TURB) followed by pathology investigation of the obtained specimen(s) is an
essential step in the treatment of NMIBC.

1

The absence of detrusor muscle
in the specimen is associated with a significantly higher risk of residual disease and
tumour understaging (with the exception of TaLG tumours).

2b

In patients with a history of
small TaLG/G1 tumours, fulguration of small papillary recurrences on an outpatient basis is
feasible and safe.

In patients suspected
of having bladder cancer, perform a TURB followed by pathology investigation of the obtained
specimen(s) as a diagnostic procedure and initial treatment step.

Strong

Outpatient
fulguration or laser vaporisation of small papillary recurrences can be used in patients
with a history of TaG1/LG tumours.

Weak

Perform TURB
systematically in individual steps:

bimanual palpation under anaesthesia. This step may be
omitted in case non-invasive or early treatment for invasive disease is planned;

insertion of the resectoscope, under visual control
with inspection of the whole urethra;

inspection of the whole urothelial lining of the
bladder;

biopsy from the prostatic urethra (if indicated);

cold-cup bladder biopsies (if indicated);

resection of the tumour;

recording of findings in the surgery
report/record;

precise description of the specimen for pathology
evaluation.

Strong

Performance of individual steps

Perform en-bloc resection or resection in fractions (exophytic
part of the tumour, the underlying bladder wall and the edges of the resection area). The
presence of detrusor muscle in the specimen is required in all cases except for TaG1/LG
tumours.

Strong

Avoid cauterisation
as much as possible during TURB to avoid tissue deterioration.

Strong

Take biopsies from
abnormal-looking urothelium. Biopsies from normal-looking mucosa (mapping biopsies from the
trigone, bladder dome, right, left, anterior and posterior bladder wall) are recommended
when cytology is positive, in case of a history of HG/G3 tumours and in tumours with
non-papillary appearance. If equipment is available, perform fluorescence-guided (PDD)
biopsies.

Strong

Take a biopsy of the
prostatic urethra in cases of bladder neck tumour, when bladder carcinoma in situ is present or suspected, when there is
positive cytology without evidence of tumour in the bladder, or when abnormalities of the
prostatic urethra are visible. If biopsy is not performed during the initial procedure, it
should be completed at the time of the second resection.

Strong

Take the biopsy from
abnormal areas in the prostatic urethra and from the precollicular area (between the 5 and 7
o’clock position) using a resection loop. In primary non-muscle-invasive tumours when
stromal invasion is not suspected, cold-cup biopsy with forceps can be used.

6.PREDICTING DISEASE RECURRENCE AND PROGRESSION

6.1.TaT1 tumours

Treatment should be based on a patient’s prognosis. In order to predict,
separately, the short- and long-term risks of disease recurrence and progression in individual
patients, the EORTC Genito-Urinary Cancer Group has developed a scoring system and risk tables [161].
The basis for these tables are individual patient data from 2,596 patients diagnosed with TaT1
tumours, who were randomised into seven EORTC trials. Patients with CIS alone were not included.
Seventy-eight percent of patients received intravesical treatment, mostly chemotherapy. However,
they did not undergo a second TURB or receive maintenance BCG.

The scoring system is based on the six most significant clinical
and pathological factors which are shown in Table 6.1. It also illustrates the weights applied to
various factors for calculating the total scores for recurrence and progression. Table 6.2 shows the
total scores stratified, into four categories that reflect various probabilities of recurrence and
progression at one and five years [161]
(LE: 2a).

Table 6.2: Probability of recurrence and disease progression according to
total score

Recurrence
score

Probability of recurrence at 1 year

Probability of
recurrence at 5 years

%

(95% CI)

%

(95% CI)

0

15

(10-19)

31

(24-37)

1-4

24

(21-26)

46

(42-49)

5-9

38

(35-41)

62

(58-65)

10-17

61

(55-67)

78

(73-84)

Progression
score

Probability of progression at 1 year

Probability of
progression at 5 years

%

(95% CI)

%

(95% CI)

0

0.2

(0-0.7)

0.8

(0-1.7)

2-6

1

(0.4-1.6)

6

(5-8)

7-13

5

(4-7)

17

(14-20)

14-23

17

(10-24)

45

(35-55)

NB: An electronic calculator for Tables 6.1 and 6.2 is
included in the EAU NMIBC Guidelines Pocket app.

The prognosis of intermediate-risk patients treated with chemotherapy has been
calculated in a recently published paper. Patients with Ta G1/G2 tumours receiving chemotherapy were
further stratified into three risk groups for recurrence, taking into account the history of
recurrences, history of intravesical treatment, tumour grade, number of tumours and adjuvant
chemotherapy [162].

A scoring model for BCG-treated patients that predicts the short- and long-term
risks of recurrence and progression has been published by the Club Urológico Espanol de Tratamiento
Oncológico (CUETO) (Spanish Urological Oncology Group). It is based on an analysis of 1,062 patients
from four CUETO trials that compared different intravesical BCG treatments. Patients received twelve
instillations over five-six months. No immediate post-operative instillation or second TURB was
performed in these patients. The scoring system is based on the evaluation of seven prognostic
factors:

gender;

age;

prior recurrence status;

number of tumours;

T category;

associated CIS;

tumour grade.

Using these tables, the calculated risk of recurrence is lower than that obtained
by the EORTC tables. For progression, probability is lower only in high-risk patients [163]
(LE: 2a). The lower risks in the CUETO tables may be attributed to the use of BCG in this sample,
which is a more effective instillation therapy.

The prognostic value of the EORTC scoring system has been
confirmed by data from the CUETO patients treated with BCG and by long-term follow up in an
independent patient population [164,165]
(LE: 2a).

In 1,812 intermediate- and high-risk patients without CIS treated with one to three
years of maintenance BCG, the EORTC found that the prior disease-recurrence rate and number of
tumours were the most important prognostic factors for disease recurrence, stage and grade were the
most important prognostic factors for disease progression and disease-specific survival, while age
and grade were the most important prognostic factors for OS. T1G3 patients do poorly, with one- and
five-year disease-progression rates of 11.4% and 19.8%, respectively. Using these data the new EORTC
risk groups and nomograms for BCG treated patients were designed [166]
(LE: 2a).

Further prognostic factors have been described in selected patient populations:

In T1G3 tumours important prognostic factors were female sex, CIS in the prostatic urethra in
men treated with an induction course of BCG, and age, tumour size and concurrent CIS in
BCG-treated patients (62% with induction course only) [133,167]
(LE: 2b).

Attention must be given to patients with T1G3 tumours in bladder (pseudo) diverticulum because
of the absence of muscle layer in the diverticular wall [168]
(LE: 3).

In patients with high-risk disease, the tumour stage at the time of the second TURB is an
unfavourable prognostic factor [154,155]
(LE: 3).

In patients with T1G2 tumours treated with TURB, recurrence at three months was the most
important predictor of progression [169]
(LE: 2b).

The prognostic value of pathological factors has been discussed elsewhere (see Section 4.6).
More research is needed to determine the role of molecular markers in improving the predictive
accuracy of currently available risk tables [164,170].

6.2.Carcinoma in situ

Without any treatment, approximately 54% of patients with CIS progress to
muscle-invasive disease [171]
(LE: 3). Unfortunately, there are no reliable prognostic factors that can be used to predict the
course of the disease. Publications are based on retrospective analyses of small series of patients
and conclusions are not homogeneous. Some studies have reported a worse prognosis in concurrent CIS
and T1 tumours compared to primary CIS [172,173],
extended CIS [174]
and CIS in the prostatic urethra [133]
(LE: 3).

The response to intravesical treatment with BCG or chemotherapy
is an important prognostic factor for subsequent progression and death caused by BC [163-165,169].
Approximately 10-20% of complete responders eventually progress to muscle-invasive disease, compared
with 66% of non-responders [175,176]
(LE: 2a).

6.3.Patient stratification into risk groups

To facilitate treatment recommendations it is important to categorise patients into
risk groups. Based on available prognostic factors and in particular data from the EORTC risk
tables, the Guidelines Panel recommends stratification of patients into three risk groups. Table 6.3
provides a definition of these risk groups, which takes into account the EORTC risk tables’
probabilities of recurrence and, especially, progression.

6.4.Subgroup of highest-risk tumours

Based on prognostic factors, it is possible to substratify high-risk group
patients, and identify those that are at the highest risk of disease progression. Patients diagnosed
with T1G3/HG tumours associated with concurrent bladder CIS, multiple- and/or large T1G3/HG tumours
and/or recurrent T1G3/HG,T1G3/HG with CIS in the prostatic urethra, some forms of variant histology
of urothelial carcinoma, and T1 tumours with LVI (Table 6.3) are at the highest risk of
progression.

Table 6.3: Risk group stratification

Risk group
stratification

Characteristics

Low-risk tumours

Primary, solitary, TaG1
(PUNLMP, LG*), < 3 cm, no CIS

Intermediate-risk tumours

All tumours not defined in the
two adjacent categories (between the category of low- and high risk).

High-risk
tumours

Any of the following:

• T1 tumour

• G3 (HG**) tumour

• carcinoma in situ (CIS)

• Multiple, recurrent and large (> 3 cm) TaG1G2 /LG
tumours (all features must be present)*.

Substratification of high-risk tumours for clinical purposes is
addressed in Table 7.2.

*Low grade is a mixture of G1 and G2.

**High grade is a mixture of some G2 and all G3 (see Figure
4.1).

6.5.Summary of evidence and guidelines for
stratification of non-muscle-invasive bladder cancer

Summary of evidence

LE

The EORTC scoring system and
risk tables predict the short- and long-term risks of disease recurrence and progression in
individual patients with non-muscle-invasive bladder cancer (NMIBC).

2a

Patients with Ta G1/G2 tumours
receiving chemotherapy have been further stratified into three risk groups for recurrence,
taking into account the history of recurrences, history of intravesical treatment, tumour
grade, number of tumours and adjuvant chemotherapy.

2a-b

In patients treated with BCG,
the CUETO scoring model predicts the short- and long-term risks of disease recurrence and
progression.

2a

In patients receiving BCG
maintenance; prior recurrence rate and number of tumours are the most important prognostic
factors for disease recurrence.

2a

Stage and grade are the most
important prognostic factors for disease progression and disease-specific survival.

2a

Patient age and grade are the
most important prognostic factors for overall survival.

2a

Recommendations

Strength
rating

Stratify patients
into three risk groups according to Table 6.3.

Strong

Apply the EORTC risk
tables and calculator for the prediction of the risk of tumour recurrence and progression in
different intervals after transurethral resection of the bladder, in individual
patients.

Strong

Use the CUETO risk
tables and the EORTC risk groups for the prediction of the risk of tumour recurrence and
progression in individual patients treated with bacillus Calmette-Guérin.

Strong

7.DISEASE MANAGEMENT

7.1.Counselling of smoking cessation

It has been confirmed that smoking increases the risk of tumour recurrence and
progression [177,178]
(LE: 3). While it is still controversial whether smoking cessation in BC will favourably
influence the outcome of BC treatment, patients should be counselled to stop smoking due to the
general risks connected with tobacco smoking [179-182]
(LE: 3).

7.2.Adjuvant treatment

7.2.1.Intravesical chemotherapy

Although TURB by itself can eradicate a TaT1 tumour completely, these tumours
commonly recur and can progress to MIBC. The high variability in the three-month recurrence rate
indicates that the TURB was incomplete or provokes recurrences in a high percentage of patients [114].
It is therefore necessary to consider adjuvant therapy in all patients.

Immediate single instillation (SI) has been shown to act by destroying circulating
tumour cells after TURB, and by an ablative effect (chemo resection) on residual tumour cells at the
resection site and on small overlooked tumours [183-186]
(LE: 3).

Four large meta-analyses comprising 1,476 to 3,103 patients have
consistently shown that after TURB, SI significantly reduces the recurrence rate compared to TURB
alone [187-190]
(LE: 1a). In the most recent systematic review and individual patient data meta-analysis of 2,278
eligible patients [187],
SI reduced the five-year recurrence rate by 14%, from 59% to 45%. The number-needed-to-treat to
prevent one recurrence within five years was seven eligible patients. Only patients with a prior
recurrence rate of less than or equal to one recurrence per year and those with an EORTC recurrence
score < 5 benefited from SI. In patients with an EORTC recurrence score > 5 and/or patients with a prior recurrence rate of
> 1 recurrence per year, SI was not effective as a single adjuvant treatment.

Single instillation with Mitomycin C (MMC), epirubicin or
pirarubicin, have all shown a beneficial effect [187].
Single instillation with gemcitabine was superior to placebo control (saline) in a recent RCT with
approximately 200 patients per arm [191],
with remarkably low toxicity rates for SI with gemcitabine [191].
These findings are in contrast with a previous study, which, however, used a shorter instillation
time [192].
In the Böhle et al. study, continuous saline irrigation was
used for 24 hours postoperatively in both arms, which could explain the low recurrence rate in the
control arm and raises questions regarding the efficacy of continuous saline irrigation in the
prevention of early recurrences [192].

No randomised comparisons of individual drugs have been conducted
[187-190]
(LE: 1a).

Prevention of tumour cell implantation should be initiated within the first few
hours after TURB. After that, tumour cells are firmly implanted and are covered by the extracellular
matrix [183,193-195]
(LE: 3). In all SI studies, the instillation was administered within 24 hours. To maximise the
efficacy of SI, one should devise flexible practices that allow the instillation to be given as soon
as possible after TURB, preferably within the first two hours in the recovery room or even in the
operating theatre. As severe complications have been reported in patients with drug extravasation
[196,197]
safety measures should be maintained (see Section 7.5).

7.2.1.2.Additional adjuvant intravesical chemotherapy instillations

The need for further adjuvant intravesical therapy depends on prognosis. In
low-risk patients (Tables 6.1, 6.2 and 6.3), a SI reduces the risk of recurrence and is considered
to be the standard and complete treatment [187,188]
(LE: 1a). For other patients, however, a SI remains an incomplete treatment because of the
considerable likelihood of recurrence and/or progression (Tables 6.1, 6.2 and 6.3).

Efficacy data for the following comparisons of application schemes were
published:

Single installation only vs. SI and further repeat instillationsIn one study, further chemotherapy instillations after SI improved RFS in intermediate-risk patients [198] (LE: 2a).

Repeat chemotherapy instillations vs. no adjuvant treatment

A large meta-analysis of 3,703 patients from eleven randomised trials showed a
highly significant (44%) reduction in the odds of recurrence at one year in favour of chemotherapy
over TURB alone [199].
This corresponds to an absolute difference of 13-14% in the number of patients with recurrence.
Contrary to these findings, two meta-analyses have demonstrated that BCG therapy may reduce the risk
of tumour progression [200,201]
(LE: 1a) (see Section 7.2.2.1). Moreover, BCG maintenance therapy appears to be significantly better
in preventing recurrences than chemotherapy [202-204]
(see Section 7.2.2.1) (LE: 1a). However, BCG causes significantly more side effects than
chemotherapy [204]
(LE: 1a).

Single instillation + further repeat instillations vs. later repeat
instillations only

There is evidence from several studies in intermediate-risk patients that SI might
have an impact on recurrence even when further adjuvant instillations are given [205-208].
A recent RCT including 2,243 NMIBC patients, which compared SI of MMC with an instillation of MMC
delayed two weeks after TURB (followed by further repeat instillations in both treatment arms),
showed a significant reduction of 9% in the risk of recurrence at three years in favour of SI, from
36% to 27%. The effect was significant in the intermediate- and high-risk groups of patients
receiving additional adjuvant MMC instillations [205]
(LE: 2a). Since the author’s definition of the risk groups differed significantly in the initial
publication, they adapted their patient stratification in the second analysis and consistently
showed improved efficacy of SI followed by repeat MMC instillations [209].
The results of this study should be considered with caution since some patients did not receive
adequate therapy (BCG in high-risk tumours).

The length and frequency of repeat chemotherapy instillations is
still controversial. A SR of RCTs, comparing different schedules of intravesical chemotherapy
instillations, concluded that the ideal duration and intensity of the schedule remains undefined
because of conflicting data [208].
The available evidence does not support treatment longer than one year (LE: 3).

7.2.1.3.Options for improving efficacy of intravesical
chemotherapy

7.2.1.3.1.Adjustment of pH,
duration of instillation, and drug concentration

One RCT using MMC has demonstrated that adapting urinary pH, decreasing urinary
excretion, and buffering the intravesical solution reduced the recurrence rate [210]
(LE: 1b). Another trial reported that duration of a one hour instillation of MCC was more effective
compared to a 30 minute instillation, but no efficacy comparisons are available for one- vs.
two-hour durations of instillation [211]
(LE: 3). Another RCT using epirubicin has documented that concentration is more important than
treatment duration [212]
(LE: 1b). In view of these data, instructions are provided (see Section 7.5).

7.2.1.3.2.Device-assisted intravesical chemotherapy

Microwave-induced hyperthermia

Promising data have been presented on enhancing the efficacy of MMC using
microwave-induced hyperthermia in patients with high-risk tumours [213].
In one RCT comparing one year of BCG with one year MMC and microwave-induced hyperthermia in
patients with intermediate- and high-risk BC, a reduced RFS at 24 months in the MMC group was
demonstrated [214]
(LE: 1b).

Hyperthermic intravesical chemotherapy

Different technologies which increase the temperature of instilled MMC are
available, however, data about their efficacy are still lacking.

Electromotive drug administration

The efficacy of MMC using electromotive drug adminstration (EMDA) sequentially
combined with BCG in patients with high-risk tumours has been demonstrated in one small RCT [215].
The definitive conclusion, however, needs further confirmation.

7.2.1.4.Summary of evidence - intravesical chemotherapy

Summary of evidence

LE

In patients with
non-muscle-invasive bladder cancer and a prior low recurrence rate (to one recurrence per
year) and in those with an EORTC recurrence score < 5, a single instillation (SI)
significantly reduces the recurrence rate compared to transurethral resection of the bladder
alone.

1a

Single instillation might have
an impact on recurrence even when further adjuvant chemotherapy instillations are given.

7.2.2.Intravesical bacillus Calmette-Guérin (BCG) immunotherapy

7.2.2.1.Efficacy of BCG

Recurrence rate Five meta-analyses have confirmed that BCG after TURB is superior to TURB alone or
TURB + chemotherapy for preventing the recurrence of NMIBC [202,216-219]
(LE: 1a). Three RCTs of intermediate- and high-risk tumours have compared BCG with epirubicin and
interferon (INF) [220],
MMC
[221],
or epirubicin alone [203]
and have confirmed the superiority of BCG for prevention of tumour recurrence (LE: 1a). The effect
is long lasting [203,221]
and was also observed in a separate analysis of patients with intermediate-risk tumours [203].
One meta-analysis [202]
has evaluated the individual data from 2,820 patients enrolled in nine RCTs that have compared MMC
vs. BCG. In the trials with BCG maintenance, there was a 32% reduction in the risk of recurrence for
BCG compared to MMC, but a 28% increase in the risk of recurrence for patients treated with BCG in
the trials without BCG maintenance.

It has been suggested that the efficacy of MMC may be improved by
optimising application through the adjustment of urine pH, in addition to the use of alternative
maintenance schedules. Neither aspect is reflected in the literature quoted above since most
published studies do not support this approach.

Progression rateTwo meta-analyses have demonstrated that BCG therapy delays and potentially lowers
the risk of tumour progression [200,201]
(LE: 1a). A meta-analysis carried out by the EORTC Genito-Urinary Cancers Group (GUCG) has evaluated
data from 4,863 patients enrolled in 24 RCTs. Five different BCG strains were used, and in 20 of the
trials, some form of BCG maintenance was used. Based on a median follow-up of 2.5 years, in 260 out
of 2,658 patients (9.8%) treated with BCG, tumours progressed, compared to 304 out of 2,205 (13.8%)
in the control groups (TURB alone, TURB and intravesical chemotherapy, or TURB with the addition of
other immunotherapy). This shows a reduction of 27% in the odds of progression with BCG maintenance
treatment. The size of the reduction was similar in patients with TaT1 papillary tumours and in
those with CIS [201].
A RCT with long-term observation has demonstrated significantly fewer distant metastases and better
overall- and disease-specific survival in patients treated with BCG compared to epirubicin [203]
(LE: 1b). In contrast, a meta-analysis of individual patient data was not able to confirm any
statistically significant difference between MMC and BCG for progression, survival and cause of
death [202].

The conflicting results in the outcomes of these studies can be
explained by different patient characteristics, duration of follow-up, methodology and statistical
power. However, most studies showed a reduction in the risk of progression in high- and
intermediate-risk tumours if BCG was applied including a maintenance schedule.

Influence of further factorsTwo other meta-analyses have suggested a possible bias in favour of BCG arising
from the inclusion of patients previously treated with intravesical chemotherapy [222].
In the IPD meta-analysis, however, BCG maintenance was more effective than MMC in reduction of
recurrence rate, both in patients previously treated and not previously treated with chemotherapy
[202]
(LE: 1a). It was demonstrated that BCG was less effective in patients > 70 years of age, but
still more effective than epirubicin in a cohort of elderly patients [223]
(LE: 1a). According to a cohort analysis, the risk of tumour recurrence after BCG was shown to be
higher in patients with a previous history of UTUC [224].

7.2.2.2.BCG strain

Although smaller studies without maintenance demonstrated some differences between
strains [224-226],
a recently published network meta-analysis identified ten different BCG strains used for
intravesical treatment in the published literature and incorporated both direct and indirect
comparisons but was not able to confirm superiority of any BCG strain over another [227].

Similarly, a published meta-analysis of prospective RCTs [201],
recently published data from a prospective registry [228]
as well as from a post-hoc analysis of a large phase 2
prospective trial assessing BCG and IFNα in both BCG naive and BCG
failure patients [229]
did not suggest any clear difference in efficacy between the different BCG strains (LE: 2a). The
quality of data, however, does not allow definitive conclusions. Further evaluation in
well-conducted prospective trials of patients receiving maintenance BCG is still needed.

7.2.2.3.BCG toxicity

Bacillus Calmette-Guérin intravesical treatment is associated with more side
effects compared to intravesical chemotherapy [201]
(LE: 1a). However, serious side effects are encountered in < 5% of patients and can be treated
effectively in almost all cases [230]
(LE: 1b). It has been shown that a maintenance schedule is not associated with an increased risk of
side effects compared to an induction course [230].
Side effects requiring treatment stoppage were seen more often in the first year of therapy [231].
Elderly patients do not seem to experience more side effects leading to treatment discontinuation
[232]
(LE: 2a). No significant difference in toxicity between different BCG strains was demonstrated [228].

Major complications can appear after systemic absorption of the
drug. Thus, contraindications of BCG intravesical instillation should be respected (see Section
7.5). The presence of leukocyturia, nonvisible haematuria or asymptomatic bacteriuria is not a
contraindication for BCG application, and antibiotic prophylaxis is not necessary in these cases [97,233,234]
(LE: 3).

Bacillus Calmette-Guérin should be used with caution in
immunocompromised patients; e.g. immunosuppression, human immunodeficiency virus [HIV] infection
pose relative contraindications [235],
although some small studies have shown similar efficacy and no increase in complications compared to
non-immunocompromised patients. The role of prophylactic anti-tuberculosis medication in these
patients remains unclear [236-238]
(LE: 3). The management of side effects after BCG should reflect their type and grade according to
the recommendations provided by the International Bladder Cancer Group (IBCG) and by a Spanish group
[239,240]
(Table 7.1).

Consider high-dose quinolones
or isoniazid and rifampicin for persistent symptoms.

Delay therapy until reactions
resolve.

7.2.2.4.Optimal BCG schedule

Induction BCG instillations are given according to the empirical six-weekly
schedule introduced by Morales et al. [244].
For optimal efficacy, BCG must be given in a maintenance schedule [200-202,219]
(LE: 1a). Many different maintenance schedules have been used, ranging from a total of ten
instillations given in eighteen weeks to 27 over three years [245].
The EORTC meta-analysis was unable to determine which BCG maintenance schedule was the most
effective [201].
In their meta-analysis, Bohle et al. concluded that at least
one year of maintenance BCG is required to obtain superiority of BCG over MMC for prevention of
recurrence or progression [200]
(LE: 1a).

The optimal number of induction instillations and the optimal
frequency and duration of maintenance instillations is not fully known. Moreover, it can be
different in each individual patient [246].
In a RCT of 1,355 patients, the EORTC has shown that when BCG is given at full dose, three years’
maintenance (three-weekly instillations 3, 6, 12, 18, 24, 30 and 36 months) reduces the recurrence
rate compared to one year in high- but not in intermediate-risk patients. There were no differences
in progression or OS. In the three-year arm, however, 36.1% of patients did not complete the
three-year schedule [247]
(LE: 1b). In a RCT of 397 patients CUETO suggested that in high-risk tumours, the maintenance
schedule with only one instillation every three months for three years may be suboptimal [248]
(LE: 1b).

7.2.2.5.Optimal dose of BCG

To reduce BCG toxicity, instillation of a reduced dose was proposed. However, it
has been suggested that a full dose of BCG is more effective in multifocal tumours [249,250]
(LE: 1b). The CUETO study compared one-third dose to full-dose BCG and found no overall difference
in efficacy. One-third of the standard dose of BCG might be the minimum effective dose for
intermediate-risk tumours. A further reduction to one-sixth dose resulted in a decrease in efficacy
with no decrease in toxicity [251]
(LE: 1b).

The EORTC did not find any difference in toxicity between
one-third and full-dose BCG, but one-third dose BCG was associated with a higher recurrence rate,
especially when it was given only for one year [231,247]
(LE: 1b). The routine use of one-third dose BCG is complicated by potential technical difficulties
in preparing the reduced dose reliably, given uneven distribution of colony-forming-units in the dry
product formulation.

7.2.2.6.Indications for
BCG

Although BCG is very effective, there is consensus that not all patients with NMIBC
should be treated with BCG due to the risk of toxicity. Ultimately, the choice of treatment depends
upon the patient’s risk (Table 6.2). Recommendations for individual risk groups are provided in
Section 7.5.

7.2.2.7.Summary of evidence - BCG treatment

Summary of evidence

LE

In patients with intermediate-
and high-risk tumours, intravesical bacillus Calmette-Guérin (BCG) after TURB reduces the
risk of tumour recurrence; it is more effective than TURB alone or TURB and intravesical
chemotherapy.

1a

For optimal efficacy, BCG must
be given in a maintenance schedule.

1a

Three-year maintenance is more
effective than one year to prevent recurrence in patients with high-risk tumours, but
not in patients with intermediate-risk tumours.

1a

7.2.3.Combination therapy

In one RCT, a combination of MMC and BCG was shown to be more effective in reducing
recurrences but more toxic compared to BCG monotherapy (LE: 1b). Using similar BCG schedules in both
groups, each BCG instillation in the combination group was preceded a day before by one MMC
instillation [252].
In a Cochrane meta-analysis of 4 RCTs including patients at high risk of recurrence and progression,
a combination of BCG and IFN-2α did not show a clear difference in
recurrence and progression over BCG alone. In one study, weekly MMC followed by monthly BCG
alternating with IFN 2α showed a higher probability of recurrence
compared to MMC followed by BCG alone [253].
Additionally, a RCT in a similar population of NMIBC comparing BCG monotherapy with a combination of
epirubicin and INF for up to two years showed the latter was significantly inferior to BCG
monotherapy in preventing recurrence [254]
(LE: 1b). In a RCT using MMC with EMDA, a combination of BCG and MMC with EMDA showed an improved
recurrence-free interval and reduced progression rate compared to BCG monotherapy [215,255]
(LE: 2).

7.2.4.Specific aspects of treatment of carcinoma in situ

7.2.4.1.Treatment strategy

The detection of concurrent CIS increases the risk of recurrence and progression of
TaT1 tumours [161,163],
in this case further treatment according to the criteria summarised in Sections 7.2.1, 7.2.2, 7.3
and 7.4 is mandatory. Carcinoma in situ cannot be cured by an
endoscopic procedure alone. Histological diagnosis of CIS must be followed by further treatment,
either intravesical BCG instillations or RC (LE: 4). Tumour-specific survival rates after immediate
RC for CIS are excellent, but a large proportion of patients might be over-treated [171]
(LE: 3).

7.2.4.2.Cohort studies on
intravesical BCG or chemotherapy

In retrospective evaluations of patients with CIS, a complete response rate of 48% was achieved with intravesical chemotherapy and 72-93% with BCG [171-174,256] (LE: 2a). Up to 50% of complete responders might eventually show recurrence with a risk of invasion and/or extravesical recurrence [174,195,245,256] (LE: 3).

Unfortunately, there have been few randomised trials in patients with CIS only. A meta-analysis of clinical trials comparing intravesical BCG to intravesical chemotherapy in patients with CIS has shown a significantly increased response rate after BCG and a reduction of 59% in the odds of treatment failure with BCG [257] (LE: 1a).

In an EORTC-GUCG meta-analysis of tumour progression, in a
subgroup of 403 patients with CIS, BCG reduced the risk of progression by 35% as compared to
intravesical chemotherapy or different immunotherapy [201]
(LE: 1b). The combination of BCG and MMC was not superior to BCG alone [258].
In summary, compared to chemotherapy, BCG treatment of CIS increases the complete response rate, the
overall percentage of patients who remain disease free, and reduces the risk of tumour progression
(LE: 1b).

7.2.4.4.Treatment of CIS in
prostatic urethra and upper urinary tract

Patients with CIS are at high risk of extravesical involvement in the UUT and in
the prostatic urethra. Solsona et al. found that 63% of 138
patients with CIS developed extravesical involvement initially or during follow-up [259].
Patients with extravesical involvement had worse survival than those with bladder CIS alone [259]
(LE: 3). In the prostate, CIS might be present only in the epithelial lining of the prostatic
urethra or in the prostatic ducts [39].
These situations should be distinguished from tumour invasion into the prostatic stroma (stage T4a
in bladder tumours), and for which immediate radical cystoprostatectomy is mandatory. Patients with
CIS in the epithelial lining of the prostatic urethra can be treated by intravesical instillation of
BCG. Transurethral resection of the prostate can improve contact of BCG with the prostatic urethra [111,260]
(LE: 3). However, potential spread of CIS has to be considered; no suprapubic trocar-placed catheter
should be used.

In patients with prostatic duct involvement, there are promising
results of BCG, but only from small series. The data are insufficient to provide clear treatment
recommendations and radical surgery should be considered [260,261]
(LE: 3). Treatment of CIS that involves the UUT is discussed in the EAU Guidelines on Urothelial
Tumours of the Upper Urinary Tract [1].

7.2.4.5.Summary of evidence - treatment of
carcinoma in situ

Summary of evidence

LE

Carcinoma in situ (CIS) cannot be cured by an endoscopic procedure
alone.

4

Compared to intravesical
chemotherapy, bacillus Calmette-Guérin treatment of CIS increases the complete response
rate, the overall percentage of patients who remain disease free, and reduces the risk of
tumour progression.

Several categories of BCG failures, broadly defined as any disease occurrence
following therapy, have been proposed (Table 7.2). Non-muscle-invasive BC presenting after BCG can
be categorized into BCG refractory, BCG relapse and BCG unresponsive. Some evidence suggests that
patients with BCG relapse have better outcomes than BCG refractory patients [262].
Recently an updated definition of BCG-unresponsive tumours was introduced to denote a subgroup of
patients at higher risk of progression for whom further BCG is not feasible [263].
This definition was developed in consultation with the FDA to allow for single-arm trials with
complete response rate and duration of response as the primary endpoint to provide primary evidence
of effectiveness to support a marketing application since no effective therapy is available for
BCG-unresponsive NMIBC [264].

Table 7.2: Categories of unsuccessful treatment with intravesical BCG

BCG
failure

Whenever a MIBC is detected
during follow-up.

BCG-refractory tumour:

1. If T1G3/HG, non-muscle-invasive papillary tumour is
present at three months [265].
Further conservative treatment with BCG is associated with increased risk of progression
[175,266]
(LE: 3).

2. If TaG3/HG or CIS (without concomitant papillary tumour)
is present at both three and six months (after a second induction course or the first
maintenance course of BCG). If patients with CIS present at three months, an additional
BCG course can achieve a complete response in > 50% of cases [39]
(LE: 3).

1.BCG refractory or T1Ta/HG BCG relapse within 6 months or
development of CIS within 12 months of last BCG exposure [263].

BCG
intolerance

Severe side effects that
prevent further BCG instillation before completing treatment [240].

* Patients with low-grade recurrence during or after
BCG treatment are not considered to be a BCG failure.

7.3.3.Treatment of BCG failure and recurrences after BCG

Treatment recommendations and options are provided in Sections 7.5 and 7.7. They
reflect the categories mentioned in Table 7.2 and tumour characteristics at the time of
recurrence.

Patients with BCG failure are unlikely to respond to further BCG
therapy; RC is therefore the preferred option. Various studies suggest that repeat-BCG therapy is
appropriate for non-high-grade and even for some high-grade recurrent tumours [268,269]
(LE: 3). Additionally, several bladder preservation strategies have been presented in the literature
which comprise intravesical immunotherapy [270],
intravesical chemotherapy (single-agent or combination therapy), device-assisted therapy (see
Section 7.2.1.3.2), combination chemo-immunotherapy (see Section 7.2.3) [271]
or gene therapy [272].

Changing from BCG to these options can yield responses in
selected cases with BCG treatment failure [268,270,271,273-279]
(LE: 3).

Treatments other than RC must be considered oncologically
inferior in patients with BCG failure at the present time [175,265,266]
(LE: 3).

Little is known about the optimal treatment in patients with
high-risk tumours who could not complete BCG instillations because of intolerance.

Non-high-grade recurrence after BCG is not considered as BCG
failure. Treatment decisions should be individualised according to tumour characteristics. It could
include chemotherapy or repeat BCG instillations, but the published evidence is very low.

7.3.4.Summary of evidence - treatment failure of intravesical therapy

Summary of evidence

LE

Prior intravesical
chemotherapy has no impact on the effect of bacillus Calmette-Guérin (BCG) instillation.

1a

Treatments other than radical
cystectomy must be considered oncologically inferior in patients with BCG failure.

3

Flowchart 7.2: Treatment strategy in recurrence during or after intravesical
BCG*

Patients who experience disease progression to muscle-invasive stage, have a worse prognosis
than those who present with ‘primary’ muscle-invasive disease [285,286].

The potential benefit of RC must be weighed against its risks, morbidity, and
impact on quality of life. It is reasonable to propose immediate RC in those patients with NMIBC who
are at highest risk of disease progression (see Section 7.6) [60,133,161,163,287]
(LE: 3).

The benefits and risks of immediate and delayed RC should be
discussed with patients, in a shared decision-making process. Individual additional prognostic
factors in T1 tumours mentioned in Sections 4.7 and 6.4 should be considered. Early RC is strongly
recommended in patients with BCG-refractory tumours, as mentioned above. A delay in RC may lead to
decreased disease-specific survival [288]
(LE: 3).

In patients in whom RC is performed before progression to MIBC,
the five-year disease-free survival rate exceeds 80% [289-291]
(LE: 3).

7.5.Guidelines for adjuvant therapy in TaT1 tumours and
for therapy of carcinoma in situ

The type of further
therapy after transurethral resection of the bladder (TURB) should be based on the risk
groups shown in Table 6.3 and Section 7.6.

Strong

In patients with
tumours presumed to be at low risk and in those presumed to be at intermediate risk with
previous low recurrence rate (less than one recurrence per year) and expected EORTC
recurrence score < 5, one immediate chemotherapy instillation is recommended.

Strong

In patients with
intermediate-risk tumours (with or without immediate instillation), one-year full-dose
bacillus Calmette-Guérin (BCG) treatment (induction plus three-weekly instillations at 3, 6
and 12 months), or instillations of chemotherapy (the optimal schedule is not known) for a
maximum of one year is recommended. The final choice should reflect the individual patient’s
risk of recurrence and progression as well as the efficacy and side effects of each
treatment modality.

Strong

In patients with
high-risk tumours, full-dose intravesical BCG for one to three years (induction plus
three-weekly instillations at 3, 6, 12, 18, 24, 30 and 36 months), is indicated. The
additional beneficial effect of the second and third years of maintenance should be weighed
against its added costs and inconveniences.

Strong

Offer transurethral
resection of the prostate, followed by intravesical instillation of BCG to patients with CIS
in the epithelial lining of the prostatic urethra.

Offer patients with
BCG-refractory tumours, who are not candidates for RC due to comorbidities, preservation
strategies (intravesical chemotherapy, chemotherapy and microwave-induced hyperthermia).

Weak

Recommendations - technical aspects for treatment

Intravesical chemotherapy

If given, administer
a single immediate instillation of chemotherapy within 24 hours after TURB.

Weak

Omit a single
immediate instillation of chemotherapy in any case of overt or suspected bladder perforation
or bleeding requiring bladder irrigation.

Strong

Give clear
instructions to the nursing staff to control the free flow of the bladder catheter at the
end of the immediate instillation.

Strong

The optimal schedule
and duration of further intravesical chemotherapy instillation is not defined; however, it
should not exceed one year.

Weak

If intravesical
chemotherapy is given, use the drug at its optimal pH and maintain the concentration of the
drug by reducing fluid intake before and during instillation.

Strong

The length of
individual instillation should be one to two hours.

Weak

BCG intravesical immunotherapy

Absolute
contraindications of BCG intravesical instillation are:

during the first two weeks after TURB;

in patients with visible haematuria;

after traumatic catheterisation;

in patients with symptomatic urinary tract
infection.

Strong

7.6.Treatment recommendations in TaT1 tumours and
carcinoma in situ according to risk stratification

Risk
category

Definition

Treatment
recommendation

Low-risk tumours

Primary, solitary, TaG1
(PUNLMP, LG), < 3 cm, no CIS

One immediate instillation of
intravesical chemotherapy after TURB.

Intermediate-risk
tumours

All tumours not defined in the
two adjacent categories (between the category of low and high risk).

In patients with previous low
recurrence rate (less than or equal to one recurrence per year) and expected EORTC
recurrence score < 5, one immediate instillation of intravesical chemotherapy after TURB.
In all patients either one-year full-dose BCG treatment (induction plus three-weekly
instillations at three, six and twelve months), or instillations of chemotherapy (the
optimal schedule is not known) for a maximum of one year.

High-risk
tumours

Any of the following:

T1 tumours;

G3 (HG) tumour;

CIS;

Multiple, recurrent and large (> 3 cm)
TaG1G2/LG tumours (all features must be present).

Intravesical full-dose BCG
instillations for one to three years or radical cystectomy (in highest-risk tumours - see below).

8.FOLLOW-UP OF PATIENTS WITH NMIBC

As a result of the risk of recurrence and progression, patients with NMIBC need
surveillance, following therapy. However, the frequency and duration of cystoscopy and imaging
follow-up should reflect the individual patient’s degree of risk. Using risk tables (see Tables 6.1
and 6.2), the short- and long-term risks of recurrence and progression in individual patients may be
predicted and the follow-up schedule adapted accordingly (see Section 8.1) [161,163].
However, recommendations for follow-up are mainly based on retrospective data and there is a lack of
randomised studies investigating the possibility of safely reducing the frequency of follow-up
cystoscopy.

When planning the follow-up schedule and methods, the following aspects should be
considered:

The prompt detection of muscle-invasive and HG/G3 non-muscle-invasive recurrence is crucial
because a delay in diagnosis and therapy can be life-threatening.

Tumour recurrence in the low-risk group is nearly always low stage and LG/G1. Small, TaG1/LG
papillary recurrence does not present an immediate danger to the patient and early detection is
not essential for successful therapy [292,293]
(LE: 2b). Fulguration of small papillary recurrences on an outpatient basis could be a safe
option that reduces the therapeutic burden [294]
(LE: 3). Multiple authors have even suggested temporary surveillance in selected cases [295-297]
(LE: 3/2a).

The first cystoscopy after TURB at three months is an important prognostic indicator for
recurrence and progression [169,175,298-300]
(LE: 1a). Therefore, the first cystoscopy should always be performed three months after TURB in
all patients with TaT1 tumours and CIS.

In tumours at low risk, the risk of recurrence after five recurrence-free years is low [299]
(LE: 3). Therefore, in low-risk tumours, after five years of follow up, discontinuation of
cystoscopy or its replacement with less-invasive methods can be considered [300].

In tumours originally intermediate- or high risk, recurrences after ten years tumour-free are
not unusual [301]
(LE: 3). Therefore, life-long follow-up is recommended [300].

The follow-up strategy must reflect the risk of extravesical recurrence (prostatic urethra in
men and UUT in both genders).

The risk of UUT recurrence increases in patients with multiple- and high-risk tumours [74]
(LE: 3).

Positive urine test results have a positive impact on the quality of follow-up cystoscopy [108]
(LE: 1b) supporting the adjunctive role of urine tests during follow-up.

In patients initially diagnosed with TaG1-2/LG BC, US of the bladder may be a mode of
surveillance in case cystoscopy is not possible or refused by the patient [302].

No non-invasive method can replace endoscopy. Follow-up is therefore based on regular cystoscopy
(see Section 5.7).

8.1.Summary of evidence and guidelines for follow-up of
patients after transurethral resection of the bladder for non-muscle-invasive bladder cancer

Summary of evidence

LE

The first cystoscopy after
transurethral resection of the bladder at 3 months is an important prognostic indicator for
recurrence and progression.

1a

The risk of upper urinary
tract recurrence increases in patients with multiple- and high-risk tumours.

3

Recommendations

Strength
rating

Base follow-up of
TaT1 tumours and carcinoma in situ (CIS) on regular
cystoscopy.

Strong

Patients with
low-risk Ta tumours should undergo cystoscopy at three months. If negative, subsequent
cystoscopy is advised nine months later, and then yearly for five years.

Weak

Patients with
high-risk tumours should undergo cystoscopy and urinary cytology at three months. If
negative, subsequent cystoscopy and cytology should be repeated every three months for a
period of two years, and every six months thereafter until five years, and then yearly.

Weak

Patients with
intermediate-risk Ta tumours should have an in-between (individualised) follow-up scheme
using cystoscopy.

Endoscopy under
anaesthesia and bladder biopsies should be performed when office cystoscopy shows suspicious
findings or if urinary cytology is positive.

Strong

During follow-up in
patients with positive cytology and no visible tumour in the bladder, mapping-biopsies or
PDD-guided biopsies (if equipment is available) and investigation of extravesical locations
(CT urography, prostatic urethra biopsy) are recommended.

Strong

In patients initially
diagnosed with TaLG/G1-2 bladder cancer, use ultrasound of the bladder during surveillance
in case cystoscopy is not possible or refused by the patient.

101.Roupret, M., et al. A
comparison of the performance of microsatellite and methylation urine analysis for predicting the
recurrence of urothelial cell carcinoma, and definition of a set of markers by Bayesian network
analysis. BJU Int, 2008. 101: 1448.

186.Oosterlinck, W., et al. A
prospective European Organization for Research and Treatment of Cancer Genitourinary Group
randomized trial comparing transurethral resection followed by a single intravesical instillation of
epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol, 1993. 149:
749.

231.Brausi, M., et al. Side effects
of Bacillus Calmette-Guerin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary
carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study
comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol, 2014.
65: 69.

232.Oddens, J.R., et al. Increasing
age is not associated with toxicity leading to discontinuation of treatment in patients with
urothelial non-muscle-invasive bladder cancer randomised to receive 3 years of maintenance bacille
Calmette-Guerin: results from European Organisation for Research and Treatment of Cancer
Genito-Urinary Group study 30911. BJU Int, 2016. 118: 423.

250.Martinez-Pineiro, J.A., et al.
Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and
progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective
randomized trial. J Urol, 2005. 174: 1242.

257.Sylvester, R.J., et al.
Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with
carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical
trials. J Urol, 2005. 174: 86.

264.BCG-Unresponsive Nonmuscle
Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry. 2018,
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation
and Research (CDER), Center for Biologics Evaluation and Research (CBER).

10.CONFLICT OF INTEREST

All members of the Non-Muscle-Invasive Bladder Cancer guidelines working group have
provided disclosure statements of all relationships that they have that might be perceived as a
potential source of a conflict of interest. This information is publically accessible through
the European Association of Urology website: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/?type=panel.

This guidelines document was developed with the financial support
of the European Association of Urology. No external sources of funding and support have been
involved. The EAU is a non-profit organisation and funding is limited to administrative assistance
and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11.CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style
guide of the journal in which the citation appears. Accordingly, the number of authors or whether,
for instance, to include the publisher, location, or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:
EAU Guidelines. Edn. presented at the EAU Annual Congress Barcelona 2019.
ISBN 978-94-92671-04-2.